Drs. Benvenga and Robbins have continued efforts to understand the biochemical basis of thyroid hormone interaction with serum lipoproteins. The T4 binding domains of the HDL apolipoproteins have common features, including one site per molecule, affinity between serum albumin (HSA) and transthyretin (TTR); relative affinities for T4 analogs similar to HSA; distinct from the lipid the cell surface receptor binding domains; N- Terminal location. We previously reported sequence homology between the T4 binding domains of apoA-I, apoE and apoB-100 and have now extended this to other HDL apos, HSA, TTR and TBG using University of Wisconsin Genetics Computer Group and GenePro version 5 programs. Of 10 apo sequences, 5 or more had identical or conserved amino acids in 24/49 positions. The most conserved region was N-terminal in positions 1-26. A conserved motif (Y, L/I/V/M, X, X, V/L/I) occupied positions 22-26. There were 15-16 conserved residues homologous to the apos in HSA, but only 9-11 in TTR and TBG (a 50% difference). A 25 a.a. stretch of HSA, was >40% homologous with the apos. Thus we have shown that there is extensive homology between T4 binding domains even in distantly related proteins. Potential physiological importance of the thyroid hormone lipoprotein interactions have been discussed in an invited review in Trends in Endocrinology and Metabolism. Our previous work demonstrated that binding to LDL facilitated the entry of thyroxine into human fibroblasts and was mediated by the apoB/apoE cell surface receptor. Experiments are in progress to extend these observations to human hepatocytes and also to determine whether the lipoproteins are involved in the exit of thyroid hormone from the cells.